Development of nitroalkene-based inhibitors to target STING-dependent inflammation
Resumen:
Stimulator of Interferon Genes (STING) is essential for the inflammatory response to cytosolic DNA. Despite that aberrant activation of STING is linked to an increasing number of inflammatory diseases, the development of inhibitors has been challenging, with no compounds in the pipeline beyond the preclinical stage. We previously identified endogenous nitrated fatty acids as novel reversible STING inhibitors. With the aim of improving the specificity and efficacy of these compounds, we developed and tested a library of nitroalkene-based compounds for in vitro and in vivo STING inhibition. The structure-activity relationship study revealed a robustly improved electrophilicity and reduced degrees of freedom of nitroalkenes by conjugation with an aromatic moiety. The lead compounds CP-36 and CP-45, featuring a β-nitrostyrene moiety, potently inhibited STING activity in vitro and relieved STING-dependent inflammation in vivo. This validates the potential for nitroalkene compounds as drug candidates for STING modulation to treat STING-driven inflammatory diseases, providing new robust leads for preclinical development.
| 2024 | |
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Stimulator of Interferon Genes Drug discovery Nitroalkene-based compounds STING inhibitors STING-associated vasculopathy with onset in infancy Interferon |
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| Inglés | |
| Universidad de la República | |
| COLIBRI | |
| https://hdl.handle.net/20.500.12008/50451 | |
| Acceso abierto | |
| Licencia Creative Commons Atribución - No Comercial - Sin Derivadas (CC - By-NC-ND 4.0) |
| _version_ | 1872864699422343168 |
|---|---|
| author | Chang, Fei |
| author2 | Gunderstofte, Camila Colussi, Nicole Pitts, Mareena Salvatore, S.R. Thielke, Anne L. Turell Novo, Lucía Alvarez, Beatriz Goldbach-Mansky, Raphaela Villacorta, Luis Holm, Christian K. Schopfer, F.J. Hansen, Anne Louise |
| author2_role | author author author author author author author author author author author author |
| author_facet | Chang, Fei Gunderstofte, Camila Colussi, Nicole Pitts, Mareena Salvatore, S.R. Thielke, Anne L. Turell Novo, Lucía Alvarez, Beatriz Goldbach-Mansky, Raphaela Villacorta, Luis Holm, Christian K. Schopfer, F.J. Hansen, Anne Louise |
| author_role | author |
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| collection | COLIBRI |
| dc.contributor.filiacion.none.fl_str_mv | Chang Fei Gunderstofte Camila Colussi Nicole Pitts Mareena Salvatore S.R. Thielke Anne L. Turell Novo Lucía Alvarez Beatriz, Universidad de la República (Uruguay). Facultad de Ciencias. Instituto de Química Biológica. Goldbach-Mansky Raphaela Villacorta Luis Holm Christian K. Schopfer F.J. Hansen Anne Louise |
| dc.creator.none.fl_str_mv | Chang, Fei Gunderstofte, Camila Colussi, Nicole Pitts, Mareena Salvatore, S.R. Thielke, Anne L. Turell Novo, Lucía Alvarez, Beatriz Goldbach-Mansky, Raphaela Villacorta, Luis Holm, Christian K. Schopfer, F.J. Hansen, Anne Louise |
| dc.date.accessioned.none.fl_str_mv | 2025-07-02T16:41:56Z |
| dc.date.available.none.fl_str_mv | 2025-07-02T16:41:56Z |
| dc.date.issued.none.fl_str_mv | 2024 |
| dc.description.abstract.none.fl_txt_mv | Stimulator of Interferon Genes (STING) is essential for the inflammatory response to cytosolic DNA. Despite that aberrant activation of STING is linked to an increasing number of inflammatory diseases, the development of inhibitors has been challenging, with no compounds in the pipeline beyond the preclinical stage. We previously identified endogenous nitrated fatty acids as novel reversible STING inhibitors. With the aim of improving the specificity and efficacy of these compounds, we developed and tested a library of nitroalkene-based compounds for in vitro and in vivo STING inhibition. The structure-activity relationship study revealed a robustly improved electrophilicity and reduced degrees of freedom of nitroalkenes by conjugation with an aromatic moiety. The lead compounds CP-36 and CP-45, featuring a β-nitrostyrene moiety, potently inhibited STING activity in vitro and relieved STING-dependent inflammation in vivo. This validates the potential for nitroalkene compounds as drug candidates for STING modulation to treat STING-driven inflammatory diseases, providing new robust leads for preclinical development. |
| dc.description.es.fl_txt_mv | Información suplementaria en: https://doi.org/10.1016/j.redox.2024.103202 |
| dc.format.extent.es.fl_str_mv | 14 h |
| dc.format.mimetype.es.fl_str_mv | application/pdf |
| dc.identifier.citation.es.fl_str_mv | Chang, F, Gunderstofte, C, Colussi, N [y otros autores]. "Development of nitroalkene-based inhibitors to target STING-dependent inflammation". Redox Biology. [en línea] 2024, 74: 103202. 14 h. DOI: 10.1016/j.redox.2024.103202 |
| dc.identifier.doi.none.fl_str_mv | 10.1016/j.redox.2024.103202 |
| dc.identifier.issn.none.fl_str_mv | 2213-2317 |
| dc.identifier.uri.none.fl_str_mv | https://hdl.handle.net/20.500.12008/50451 |
| dc.language.iso.none.fl_str_mv | en eng |
| dc.publisher.es.fl_str_mv | Elsevier |
| dc.relation.none.fl_str_mv | Redox Biology, 2024, 74: 103202. |
| dc.rights.license.none.fl_str_mv | Licencia Creative Commons Atribución - No Comercial - Sin Derivadas (CC - By-NC-ND 4.0) |
| dc.rights.none.fl_str_mv | info:eu-repo/semantics/openAccess |
| dc.source.none.fl_str_mv | reponame:COLIBRI instname:Universidad de la República instacron:Universidad de la República |
| dc.subject.es.fl_str_mv | Stimulator of Interferon Genes Drug discovery Nitroalkene-based compounds STING inhibitors STING-associated vasculopathy with onset in infancy Interferon |
| dc.title.none.fl_str_mv | Development of nitroalkene-based inhibitors to target STING-dependent inflammation |
| dc.type.es.fl_str_mv | Artículo |
| dc.type.none.fl_str_mv | info:eu-repo/semantics/article |
| dc.type.version.none.fl_str_mv | info:eu-repo/semantics/publishedVersion |
| description | Información suplementaria en: https://doi.org/10.1016/j.redox.2024.103202 |
| eu_rights_str_mv | openAccess |
| format | article |
| id | COLIBRI_651cecf2a34cd0de2121c2c71a4d30f4 |
| identifier_str_mv | Chang, F, Gunderstofte, C, Colussi, N [y otros autores]. "Development of nitroalkene-based inhibitors to target STING-dependent inflammation". Redox Biology. [en línea] 2024, 74: 103202. 14 h. DOI: 10.1016/j.redox.2024.103202 2213-2317 10.1016/j.redox.2024.103202 |
| instacron_str | Universidad de la República |
| institution | Universidad de la República |
| instname_str | Universidad de la República |
| language | eng |
| language_invalid_str_mv | en |
| network_acronym_str | COLIBRI |
| network_name_str | COLIBRI |
| oai_identifier_str | oai:colibri.udelar.edu.uy:20.500.12008/50451 |
| publishDate | 2024 |
| reponame_str | COLIBRI |
| repository.mail.fl_str_mv | karina.camps@seciu.edu.uy |
| repository.name.fl_str_mv | COLIBRI - Universidad de la República |
| repository_id_str | 4771 |
| rights_invalid_str_mv | Licencia Creative Commons Atribución - No Comercial - Sin Derivadas (CC - By-NC-ND 4.0) |
| spelling | Chang FeiGunderstofte CamilaColussi NicolePitts MareenaSalvatore S.R.Thielke Anne L.Turell Novo LucíaAlvarez Beatriz, Universidad de la República (Uruguay). Facultad de Ciencias. Instituto de Química Biológica.Goldbach-Mansky RaphaelaVillacorta LuisHolm Christian K.Schopfer F.J.Hansen Anne Louise2025-07-02T16:41:56Z2025-07-02T16:41:56Z2024Chang, F, Gunderstofte, C, Colussi, N [y otros autores]. "Development of nitroalkene-based inhibitors to target STING-dependent inflammation". Redox Biology. [en línea] 2024, 74: 103202. 14 h. DOI: 10.1016/j.redox.2024.1032022213-2317https://hdl.handle.net/20.500.12008/5045110.1016/j.redox.2024.103202Información suplementaria en: https://doi.org/10.1016/j.redox.2024.103202Stimulator of Interferon Genes (STING) is essential for the inflammatory response to cytosolic DNA. Despite that aberrant activation of STING is linked to an increasing number of inflammatory diseases, the development of inhibitors has been challenging, with no compounds in the pipeline beyond the preclinical stage. We previously identified endogenous nitrated fatty acids as novel reversible STING inhibitors. With the aim of improving the specificity and efficacy of these compounds, we developed and tested a library of nitroalkene-based compounds for in vitro and in vivo STING inhibition. The structure-activity relationship study revealed a robustly improved electrophilicity and reduced degrees of freedom of nitroalkenes by conjugation with an aromatic moiety. The lead compounds CP-36 and CP-45, featuring a β-nitrostyrene moiety, potently inhibited STING activity in vitro and relieved STING-dependent inflammation in vivo. This validates the potential for nitroalkene compounds as drug candidates for STING modulation to treat STING-driven inflammatory diseases, providing new robust leads for preclinical development.Submitted by Pintos Natalia (nataliapintosmvd@gmail.com) on 2025-06-12T11:01:00Z No. of bitstreams: 2 license_rdf: 26539 bytes, checksum: 3b50ae24bd8bd076d49a70878a8a2d2c (MD5) 10.1016-j.redox.2024.103202.pdf: 10820694 bytes, checksum: 1898f8bd7aa28d0e15d352d2f3f3b9a4 (MD5)Approved for entry into archive by Faget Cecilia (lfaget@fcien.edu.uy) on 2025-07-02T12:22:17Z (GMT) No. of bitstreams: 2 license_rdf: 26539 bytes, checksum: 3b50ae24bd8bd076d49a70878a8a2d2c (MD5) 10.1016-j.redox.2024.103202.pdf: 10820694 bytes, checksum: 1898f8bd7aa28d0e15d352d2f3f3b9a4 (MD5)Made available in DSpace by Camps Karina (karina.camps@seciu.edu.uy) on 2025-07-02T16:41:56Z (GMT). No. of bitstreams: 2 license_rdf: 26539 bytes, checksum: 3b50ae24bd8bd076d49a70878a8a2d2c (MD5) 10.1016-j.redox.2024.103202.pdf: 10820694 bytes, checksum: 1898f8bd7aa28d0e15d352d2f3f3b9a4 (MD5) Previous issue date: 202414 happlication/pdfenengElsevierRedox Biology, 2024, 74: 103202.Las obras depositadas en el Repositorio se rigen por la Ordenanza de los Derechos de la Propiedad Intelectual de la Universidad de la República.(Res. Nº 91 de C.D.C. de 8/III/1994 – D.O. 7/IV/1994) y por la Ordenanza del Repositorio Abierto de la Universidad de la República (Res. Nº 16 de C.D.C. de 07/10/2014)info:eu-repo/semantics/openAccessLicencia Creative Commons Atribución - No Comercial - Sin Derivadas (CC - By-NC-ND 4.0)Stimulator of Interferon GenesDrug discovery Nitroalkene-based compoundsSTING inhibitorsSTING-associated vasculopathy with onset in infancyInterferonDevelopment of nitroalkene-based inhibitors to target STING-dependent inflammationArtículoinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionreponame:COLIBRIinstname:Universidad de la Repúblicainstacron:Universidad de la RepúblicaChang, FeiGunderstofte, CamilaColussi, NicolePitts, MareenaSalvatore, S.R.Thielke, Anne L.Turell Novo, LucíaAlvarez, BeatrizGoldbach-Mansky, RaphaelaVillacorta, LuisHolm, Christian K.Schopfer, F.J.Hansen, Anne LouiseLICENSElicense.txtlicense.txttext/plain; charset=utf-84267http://localhost:8080/xmlui/bitstream/20.500.12008/50451/5/license.txt6429389a7df7277b72b7924fdc7d47a9MD55CC-LICENSElicense_urllicense_urltext/plain; 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públicahttps://udelar.edu.uy/https://www.colibri.udelar.edu.uy/oai/requestkarina.camps@seciu.edu.uyUruguayopendoar:47712025-07-02T16:41:56COLIBRI - Universidad de la Repúblicafalse |
| spellingShingle | Development of nitroalkene-based inhibitors to target STING-dependent inflammation Chang, Fei Stimulator of Interferon Genes Drug discovery Nitroalkene-based compounds STING inhibitors STING-associated vasculopathy with onset in infancy Interferon |
| status_str | publishedVersion |
| title | Development of nitroalkene-based inhibitors to target STING-dependent inflammation |
| title_full | Development of nitroalkene-based inhibitors to target STING-dependent inflammation |
| title_fullStr | Development of nitroalkene-based inhibitors to target STING-dependent inflammation |
| title_full_unstemmed | Development of nitroalkene-based inhibitors to target STING-dependent inflammation |
| title_short | Development of nitroalkene-based inhibitors to target STING-dependent inflammation |
| title_sort | Development of nitroalkene-based inhibitors to target STING-dependent inflammation |
| topic | Stimulator of Interferon Genes Drug discovery Nitroalkene-based compounds STING inhibitors STING-associated vasculopathy with onset in infancy Interferon |
| url | https://hdl.handle.net/20.500.12008/50451 |
